中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (4): 911-919.doi: 10.4103/1673-5374.322473

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

加权基因共表达网络分析轴突再生与华勒变性在协同调节周围神经损伤的修复机制

  

  • 出版日期:2022-04-15 发布日期:2021-10-18

Identification of key genes involved in axon regeneration and Wallerian degeneration by weighted gene co-expression network analysis

Yan Lu1, #, Qi Shan1, #, Mei Ling2, Xi-An Ni1, Su-Su Mao1, Bin Yu1, *, Qian-Qian Cao1, *   

  1. 1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 2School of Life Sciences, Nantong University, Nantong, Jiangsu Province, China
  • Online:2022-04-15 Published:2021-10-18
  • Contact: Qian-Qian Cao, PhD, cqq09100239@163.com; Bin Yu, PhD, yubin@ntu.edu.cn
  • Supported by:
    This study was supported by the National Major Project of Research and Development of China, No. 2017YFA0104701 (to BY); the National Natural Science Foundation of China, No. 32000725 (to QQC); the Natural Science Foundation of Jiangsu Province of China, No. BK20200973 (to QQC); and the Jiangsu Provincial University Innovation Training Key Project of China, No. 202010304021Z (to ML). 

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摘要：

成功的神经修复需要轴突再生和华勒变性在一定程度上的协作。因此，了解轴突再生和变性如何协调周围神经损伤修复的机制可能为揭示周围神经修复的分子机制和信号级联提供了新的视角，并可为改善中枢神经系统近端轴突再生能力的缺乏提供潜在策略。为此，实验应用加权基因共表达网络分析比较大鼠损伤坐骨神经近端和远端差异表达的基因。结果从损伤神经的近端和远端神经节段中分别鉴定了31个和15个共表达模块。进一步功能富集分析表明，近端模块的差异表达基因参与了促神经再生的生物学通路，而远端模块的差异表达基因则参与了促神经退变的生物学通路。从构建的基因网络中筛选了中枢基因，可见其中一个中枢基因Kif22在近端和远端神经节段均表达上调。体外实验证实敲低Kif22基因可抑制许旺细胞的增殖，通过细胞外调节蛋白激酶信号通路迁移。总之研究得出了损伤周围神经近端和远端神经节段共表达基因模块的比较框架，并确定了Kif22是许旺细胞参与周围神经修复的潜在靶点。实验于2021年3月22日经南通大学动物伦理委员会批准（批准号S20210322-008）。

https://orcid.org/0000-0002-9677-6916 (Qian-Qian Cao); https://orcid.org/0000-0002-8927-3333 (Bin Yu)

关键词: 周围神经损伤, 轴突再生, 华勒变性, 加权基因共表达网络分析, 中枢基因, Kif22, 许旺细胞, 蛋白激酶Cα, 细胞外调节蛋白激酶

Abstract: Peripheral nerve injury repair requires a certain degree of cooperation between axon regeneration and Wallerian degeneration. Therefore, investigating how axon regeneration and degeneration work together to repair peripheral nerve injury may uncover the molecular mechanisms and signal cascades underlying peripheral nerve repair and provide potential strategies for improving the low axon regeneration capacity of the central nervous system. In this study, we applied weighted gene co-expression network analysis to identify differentially expressed genes in proximal and distal sciatic nerve segments from rats with sciatic nerve injury. We identified 31 and 15 co-expression modules from the proximal and distal sciatic nerve segments, respectively. Functional enrichment analysis revealed that the differentially expressed genes in proximal modules promoted regeneration, while the differentially expressed genes in distal modules promoted neurodegeneration. Next, we constructed hub gene networks for selected modules and identified a key hub gene, Kif22, which was up-regulated in both nerve segments. In vitro experiments confirmed that Kif22 knockdown inhibited proliferation and migration of Schwann cells by modulating the activity of the extracellular signal-regulated kinase signaling pathway. Collectively, our findings provide a comparative framework of gene modules that are co-expressed in injured proximal and distal sciatic nerve segments, and identify Kif22 as a potential therapeutic target for promoting peripheral nerve injury repair via Schwann cell proliferation and migration. All animal experiments were approved by the Institutional Animal Ethics Committee of Nantong University, China (approval No. S20210322-008) on March 22, 2021.

Key words: axon regeneration, extracellular signal-regulated kinase signaling pathway, hub genes, Kif22, peripheral nerve injury, protein kinase Cα, Schwann cells, Wallerian degeneration, weighted gene co-expression network analysis

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